Radiobiological issues in proton therapy

Abstract

Background The relative biological effectiveness (RBE) for particle therapy is a complex function of particle type, radiation dose, linear energy transfer (LET), cell type, endpoint, etc. In the clinical practice of proton therapy, the RBE is assumed to have a fixed value of 1.1. This assumption, along with the effects of physical uncertainties, may mean that the biologically effective dose distributions received by the patient may be significantly different from what is seen on treatment plans. This may contribute to unforeseen toxicities and/or failure to control the disease. Variability of Proton RBE It has been shown experimentally that proton RBE varies significantly along the beam path, especially near the end of the particle range. While there is now an increasing acceptance that proton RBE is variable, there is an ongoing debate about whether to change the current clinical practice. Clinical Evidence A rationale against the change is the uncertainty in the models of variable RBE. Secondly, so far there is no clear clinical evidence of the harm of assuming proton RBE to be 1.1. It is conceivable, however, that the evidence is masked partially by physical uncertainties. It is, therefore, plausible that reduction in uncertainties and their incorporation in the estimation of dose actually delivered may isolate and reveal the variability of RBE in clinical practice. Nevertheless, clinical evidence of RBE variability is slowly emerging as more patients are treated with protons and their response data are analyzed. Modelling and Incorporation of RBE in the Optimization of Proton Therapy The improvement in the knowledge of RBE could lead to better understanding of outcomes of proton therapy and in the improvement of models to predict RBE. Prospectively, the incorporation of such models in the optimization of intensity-modulated proton therapy could lead to improvements in the therapeutic ratio of proton therapy.

Is the dose‐averaged LET a reliable predictor for the relative biological effectiveness?

“…For protons, according to Figs. and , our model calculations predict that the RBE in the Bragg peak and SOBP region is underestimated by using only LET D rather than the complete LET distribution; this is in line with conclusions reported by Mohan et al . and Chaudhary et al.…”

Exploring the advantages of intensity-modulated proton therapy: experimental validation of biological effects using two different beam intensity-modulation patterns

“…The use of RBE 1.1 is increasingly questioned. Now, it is well known that proton RBE is a complex function of many physical and biological factors such as dose, cell and tissue types, beam quality, and biological endpoint [9][10][11] . Nevertheless, the spatially variable RBE has yet been applied clinically in the optimization of treatment plans.…”

MultiRBE: Treatment planning for protons with selective radiobiological effectiveness

“…These new findings (along with accumulated clinical experience) have triggered several reviews of the existing knowledge on proton RBE. While a few of them claim, in one way or another, that a variable RBE scheme should be implemented in clinical practice in the near future many others agree that current evidence still does not support such a change of paradigm and propose alternative solutions for the consideration of this effect . In fact, the conclusions of a recent “expert group” explicitly mention that “the clinical practice of using a fixed RBE of 1.1 cannot be abandoned based on high‐quality evidence favoring other values in specific situations,” although they call for further research as the increasing capability to accurately deliver the dose in the treatment will cause the proton Bragg peaks to be positioned more precisely at the same spot, resulting in repeated exposure of areas with elevated LET values.…”